US8716217B2 - Polyglutamic acids functionalized by cationic groups and hydrophobic groups and applications thereof, in particular therapeutic applications thereof - Google Patents
Polyglutamic acids functionalized by cationic groups and hydrophobic groups and applications thereof, in particular therapeutic applications thereof Download PDFInfo
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- US8716217B2 US8716217B2 US12/149,542 US14954208A US8716217B2 US 8716217 B2 US8716217 B2 US 8716217B2 US 14954208 A US14954208 A US 14954208A US 8716217 B2 US8716217 B2 US 8716217B2
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- 0 [10*]C(CC1=CNC=N1)NC Chemical compound [10*]C(CC1=CNC=N1)NC 0.000 description 16
- IVGVGDMPMYWLNB-POQQNYLNSA-N [Cl-].[H]CC(CCC(=O)O[Na])C(=O)NC(CCC(=O)NC(CCCNC(=N)[NH3+])C(N)=O)C(=O)CC(CCC([3H])=O)C(N)=O Chemical compound [Cl-].[H]CC(CCC(=O)O[Na])C(=O)NC(CCC(=O)NC(CCCNC(=N)[NH3+])C(N)=O)C(=O)CC(CCC([3H])=O)C(N)=O IVGVGDMPMYWLNB-POQQNYLNSA-N 0.000 description 5
- LDSDFDLHWVCFRI-UBFYDBQFSA-N [Cl-].[H]NC(CCC(=O)O[Na])C(=O)CC(CCC(=O)NCCO)C(=O)NC(CCC(=O)NC(CCCNC(=N)[NH3+])C(N)=O)C(=O)CC(CCC([3H])=O)C(N)=O Chemical compound [Cl-].[H]NC(CCC(=O)O[Na])C(=O)CC(CCC(=O)NCCO)C(=O)NC(CCC(=O)NC(CCCNC(=N)[NH3+])C(N)=O)C(=O)CC(CCC([3H])=O)C(N)=O LDSDFDLHWVCFRI-UBFYDBQFSA-N 0.000 description 3
- GIKASUXUWOCJMJ-UHFFFAOYSA-N C.CCC(CCCNC(C)=N)C(=O)[RaH].CCCCC(CC)C(=O)[RaH].CCCCCC(C)CC Chemical compound C.CCC(CCCNC(C)=N)C(=O)[RaH].CCCCC(CC)C(=O)[RaH].CCCCCC(C)CC GIKASUXUWOCJMJ-UHFFFAOYSA-N 0.000 description 1
- LURCMDRQPWWSSG-UHFFFAOYSA-N C.CCCCC(CC)C(=O)[RaH].CCCCCC(CC)C(=O)[RaH] Chemical compound C.CCCCC(CC)C(=O)[RaH].CCCCCC(CC)C(=O)[RaH] LURCMDRQPWWSSG-UHFFFAOYSA-N 0.000 description 1
- XVZYRJBTNQVWOJ-UHFFFAOYSA-N CCC(CCCNC(C)=N)C(=O)[RaH] Chemical compound CCC(CCCNC(C)=N)C(=O)[RaH] XVZYRJBTNQVWOJ-UHFFFAOYSA-N 0.000 description 1
- DRTLWHMGGCRKBM-VAHWTKJXSA-N [Cl-].[H]CC(CCC(=O)O[Na])C(=O)NC(CCC(=O)NCCCC[NH3+])C(=O)CC(CCC([3H])=O)C(N)=O Chemical compound [Cl-].[H]CC(CCC(=O)O[Na])C(=O)NC(CCC(=O)NCCCC[NH3+])C(=O)CC(CCC([3H])=O)C(N)=O DRTLWHMGGCRKBM-VAHWTKJXSA-N 0.000 description 1
- OXWDQWGVELQADH-YFGCWADTSA-N [Cl-].[H]NC(CCC(=O)O[Na])C(=O)CC(CCC(=O)NCCO)C(=O)NC(CCC(=O)NCCCC[NH3+])C(=O)CC(CCC([3H])=O)C(N)=O Chemical compound [Cl-].[H]NC(CCC(=O)O[Na])C(=O)CC(CCC(=O)NCCO)C(=O)NC(CCC(=O)NCCCC[NH3+])C(=O)CC(CCC([3H])=O)C(N)=O OXWDQWGVELQADH-YFGCWADTSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
- C08G69/10—Alpha-amino-carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/48—Polymers modified by chemical after-treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
Definitions
- the present invention relates to novel biodegradable materials containing copolyamino acids useful in particular in the vectorization of active principle(s) (APs).
- APs active principle(s)
- the invention is also directed to novel pharmaceutical, cosmetic, health food or plant-protection compositions containing these modified polyamino acids.
- These compositions can be of a type that makes possible the vectorization of APs and are preferably provided in the form of emulsions, micelles, nanoparticles, microparticles, gels, implants or films.
- Suitable APs are advantageously biologically active compounds which can be administered to an animal or human organism using the oral, parenteral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal, intracerebral or buccal route and the like.
- APs to which the invention more particularly but without limitation relates to are proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligo- or polynucleotides, and organic molecules.
- cosmetic products or plant-protection products such as herbicides, insecticides, fungicides, and the like, are also envisioned.
- polymers include polylactic, polylactic/glycolic, polyoxyethylene/oxypropylene, polyamino acid or polysaccharide polymers. These polymers are used as starting materials, for example, for the manufacture of bulk implants, microparticles, nanoparticles, vesicles, micelles or gels. Apart from the fact that these polymers have to be suitable for the manufacture of such systems, they also have to be biocompatible, nontoxic, nonimmunogenic and economic, and they have to be able to be easily eliminated from the body and/or to be biodegradable. With regard to the latter aspect, it is moreover essential for the biodegradation in the body to generate nontoxic products.
- U.S. Pat. No. 4,652,441 describes polylactide microcapsules encapsulating the hormone LH-RH. These microcapsules are produced by preparing a water-in-oil-in-water emulsion comprising an aqueous internal layer comprising the hormone, a substance (gelatin) which fixes the latter, an oily polylactide layer and an aqueous external layer (polyvinyl alcohol). The release of the AP can take place over a period of more than two weeks after subcutaneous injection.
- U.S. Pat. No. 4,351,337 describes amphiphilic copolyamino acids based on leucine and on glutamate which can be used in the form of implants or of microparticles for the controlled release of active principles. Release of the active principles can take place over a very long period of time depending on the rate of decomposition of the polymer.
- U.S. Pat. No. 4,888,398 describes polymers based on polyglutamate or polyaspartate and optionally polyleucine with alkyloxycarbonylmethyl groups placed randomly on the polyamino acid chain. These polyamino acids, grafted with side groups, e.g. methoxycarbonylmethyl groups, can be used in the form of biodegradable implants comprising an AP for sustained release.
- U.S. Pat. No. 5,904,936 describes nanoparticles obtained from a polyleucine/polyglutamate block polymer which are able to form stable colloidal suspensions and which are capable of joining together spontaneously with biologically active proteins without denaturing them. The active proteins can subsequently be released in vivo in a controlled manner over a long period.
- U.S. Pat. No. 5,449,513 describes amphiphilic block copolymers comprising a polyoxyethylene block and a polyamino acid block, for example poly( ⁇ -benzyl-L-aspartate). These polyoxyethylene/polybenzylaspartate polymers form micelles which are capable of encapsulating hydrophobic active molecules, such as doxorubicin or indomethacin.
- Patent application WO-A-99/61512 describes polylysines and polyornithines functionalized with a hydrophobic group (palmitic acid connected to the polylysine or -ormithine) and a hydrophilic group (polyoxyethylene).
- These polymers for example polylysine grafted with polyoxyethylene and palmitoyl chains, form, in the presence of cholesterol, vesicles capable of encapsulating doxorubicin or DNA.
- These polymers based on polylysines are cationic in physiological medium.
- Patent application EP-A-963 758 describes polyamino acids functionalized by a cationic group. These polymers are capable of forming complexes with a nucleic acid and can be used in gene therapy.
- the cationic groups are amine derivatives which are not derived from amino acids and the polyamino acids do not comprise hydrophobic groups.
- Application WO-A-2004/013206 describes anionic polyamino acids comprising hydrophobic groups, wherein these groups are connected to the polymer via a joint comprising two amide functional groups and more specifically via a spacer of lysine or ornithine.
- Application WO-A-2004/060968 describes polyamino acids functionalized by at least one oligoamino acid group based on leucine, isoleucine, valine and/or phenylalanine.
- the invention relates to biodegradable polyamino acids which can be converted into colloidal nano- or microparticles for vectorization that can reversibly undergo association with active principles.
- one of the essential objectives of the present invention is to provide novel amphiphilic copolyglutamates comprising both positive charges at neutral pH or pH close to neutrality and hydrophobic groups as a pendant (or hanging) chain.
- polymers represent an improvement, with respect to those described in the patents or patent applications mentioned above, in terms of vectorization of an active principle, such as a therapeutic peptide or protein, a DNA, an RNA or a small molecule.
- Another objective of the present invention is for these polymers to be useful in the vectorization of active principles (APs) and to optimally satisfy all the specifications of the requirements, namely, in particular:
- the present invention relates to polyamino acids, or pharmaceutically acceptable salts thereof, comprising glutamic residues, wherein some of the glutamic residues each carry a pendant cationic group which, if it can be deprotonated, exhibits a pKa equal to or greater than 7, said cationic groups being identical to or different from one another, and wherein other glutamic residues each carry a pendant hydrophobic group (GH), said hydrophobic groups (GH) being identical to or different from one another.
- cationic group will generally denote cationic groups which cannot be deprotonated and cationic groups which can be deprotonated and which exhibit a pKa equal to or greater than 7.
- pharmaceutically acceptable salts of a polyamino acid according to the invention is understood to encompass all polyamino acids with counterions associated with ionized functions of the polymers.
- small molecule is understood to mean a molecule with a molecular weight of less than 1 kDa.
- alkyl groups contain 1 to 10 carbon atoms.
- Each polyglutamate according to the invention is thus functionalized by a multiplicity of pendant cationic groups that are identical to or different from one another and pendant hydrophobic groups (GH) that are identical to or different from one another.
- GH pendant hydrophobic groups
- the term “multiplicity” means that the polyglutamate is functionalized by:
- the expression “to carry” means that the group being carried is pendant, that is to say that said group is a side group with respect to glutamic residues and is a substituent of the functional carbonyl group in the ⁇ position of the glutamic residue which carries it.
- Polyglutamates of the invention also carries cationic groups. These groups are preferably attached to the glutamic residues via an amide or ester bond.
- other glutamic residues can each carry a pendant nonionizable group, different from the hydrophobic groups (GH), said nonionizable groups being identical to or different from one another.
- a pendant nonionizable group can be, for example, a hydroxyethylamino group.
- other glutamic residues can each carry, also in the ⁇ position to the carbonyl, a group which is nonionized at neutral pH, different from the hydrophobic groups (GH), said groups nonionized at neutral pH being identical to or different from one another.
- a group may have the following formula:
- —R 10 is —H, —CO 2 H, alkyl ester (preferably —COOMe or —COOEt), —CH 2 OH, —C( ⁇ O)—NH 2 , —C( ⁇ O)—NH—CH 3 or C( ⁇ O)—N(CH 3 ) 2 .
- Polyglutamates simultaneously carrying cationic groups and hydrophobic groups and, optionally, nonionic groups (nonionizable or nonionized at neutral pH), can also comprise negative charges (at neutral pH) resulting from ionization of pendant groups of the polyglutamic acid which have not been functionalized.
- the Applicant has developed a novel family of polymers based on polyglutamate carrying cationic groups and functionalized by a multiplicity of hydrophobic groups, which can form stable colloidal systems.
- the possibility to adjust the loading of the polymer as a function of the degree of functionalization can prove to be very effective in:
- polymers of the invention can be:
- polymers of the present invention undergo easy degradation in the presence of enzymes leading to nontoxic catabolites/metabolites (amino acids).
- association means that the active principle or principles is/are bonded or linked to the polyglutamate(s) in particular via a hydrophobic interaction and/or are encapsulated by the polyglutamate(s).
- polyamino acids according to the invention are L-glutamate or L-glutamic homopolymers; preferably, within the polyamino acid, these residues are linked by their carboxyl group in alpha position.
- the cationic groups which can be used to functionalize the glutamate units are identical to or different from one another and have to the following general formula:
- the cationic groups are obtained from compounds selected from the group consisting of: lysine, ornithine, arginine and their derivatives, choline, ethanolamine (linked via the oxygen atom), putrescine and agmatine.
- the lysine, ornithine and arginine derivatives can, for example, be ethyl and methyl esters, amides and methylated amides.
- cationic groups which can be used in the present invention, can be selected from the following group:
- cationic groups which can be used in the present invention, can have the following formulae (wherein the name of the precursor is indicated below each group):
- Ra represents a hydroxy, alkoxy or alkylamino group, preferably an —OMe, —OEt, —NH 2 , —NHCH 3 or —N(CH 3 ) 2 group.
- the polyamino acids of the invention comprise, on average, at least 3 hydrophobic groups (GH) per polymer chain.
- At least one of the hydrophobic groups GH is included in a hydrophobic graft comprising at least one spacing joint (or unit) (spacer) which makes it possible to link a hydrophobic group GH to a polyglutamate chain (for example, a polyglutamate backbone main chain).
- This joint can comprise, e.g., at least one direct covalent bond and/or at least one amide bond and/or at least one ester bond.
- the joint can belong to the group consisting in particular of: “amino acid” residues other than the constituent monomeric unit of the polyglutamate, aminoalcohol derivatives, polyamine (for example diamine) derivatives, polyol (for example diol) derivatives and hydroxy acid derivatives.
- the grafting of GHs to a polyglutamate chain can involve the use of GH precursors that can be attached to the polyglutamate chain.
- Precursors of GHs can be, in practice and without limitation, selected from the group consisting of alcohols and amines, these compounds being easily functionalized by a person skilled in the art.
- the grafting of GHs is disclosed in more detail below in the description of the process for obtaining modified polyamino acids according to the invention.
- a hydrophobic group GH of a hydrophobic graft comprises from 8 to 30 carbon atoms.
- hydrophobic grafts can be di-, tri- or tetravalent joints (indeed even pentavalent and more).
- a divalent joint the hydrophobic graft comprises a single GH group, whereas a trivalent joint confers a bifid nature to the hydrophobic graft, that is to say that the graft exhibits two GH “arms”.
- trivalent joints include, but are not limited to, “amino acid” residues, for example “glutamic acid”, or polyol residues, for example glycerol.
- two advantageous but nonlimiting examples of hydrophobic grafts comprising bifid GHs are dialkylglycerols and dialkyl glutamates.
- Hydrophobic groups GH can, for example, be derived from groups chosen from the group consisting of: octanol, dodecanol, tetradecanol, hexadecanol, octadecanol, oleyl alcohol, tocopherol and cholesterol.
- polyglutamates according to the invention can also carry at least one graft of polyalkylene (preferably polyethylene) glycol type linked to a glutamate residue.
- the backbone of a polyglutamate according to the present invention comprises ⁇ -L-glutamate and/or ⁇ -L-glutamic acid units.
- polyglutamates according to the invention have to the following formula (I):
- —R 10 is —H, —CO 2 H, an alkyl ester (preferably —COOMe or —COOEt), —CH 2 OH, —C( ⁇ O)—NH 2 , —C( ⁇ O)—NH—CH 3 or —C( ⁇ O)—N(CH 3 ) 2 ;
- the hydrophobic groups GH and cationic groups are arranged randomly as pendant groups.
- the molar degree of grafting of hydrophobic units of the polyglutamates according to the invention is between 2 and 99% and preferably between 5 and 50%, provided that each polymer chain has, on average, at least 3 hydrophobic grafts.
- the ratio (q)/(p+q+r+s) of the polyglutamates according to the invention means that they can comprise from 1 to approximately 97 molar % of groups comprising a cationic charge.
- the ratio (s)/(p+q+r+s) of the polyglutamates according to the invention means that they can be anionic, neutral or cationic at neutral pH.
- the polymers according to the invention have a molar mass between 2 000 and 200 000 g/mol and preferably between 5000 and 100 000 g/mol.
- the invention also encompasses mixtures of modified polyamino acids as defined above.
- polyglutamates of the invention can be used in several ways depending on the nature of the hydrophobic groups and the cationic groups, as well as the charge and the degree of polymerization of the polyglutamate.
- Methods for forming a polymer for the encapsulation of an active principle in the various forms contemplated by the invention are known to a person skilled in the art. For further details, see, for example, these few particularly relevant references:
- Polyglutamates of the invention can easily associate with or encapsulate active principles, such as proteins, peptides, DNA, RNA or small molecules.
- active principles such as proteins, peptides, DNA, RNA or small molecules.
- the preferred mode of formation is that described in U.S. Pat. No. 6,630,171 delivered to the Applicant, which consists in dispersing the copolymer in water and in incubating the solution in the presence of an active principle (AP).
- AP active principle
- the colloidal solution of vectorization particles composed of the polyglutamates according to the invention can subsequently be filtered through a 0.2 ⁇ m filter and then directly injected into a patient.
- polymer is cationic and soluble in acidic pH due to an excess of cationic charge and that this charge is partially or completely neutralized at neutral pH, such a polymer is said to be dependent on the pH.
- This type of polymer can thus be used to form a deposit after administration, for example in the subcutaneous tissue.
- the residual functional carboxyl groups of a modified polyglutamate are either neutral (COOH form) or ionized (COO ⁇ anion), depending on the pH and the composition. So, both terms i) glutamate residue or residue of glutamic acid, ii) polyglutamic acid or of polyglutamate can be used interchangeably.
- the countercation can be a metal cation, such as sodium, calcium or magnesium, or an organic cation, such as triethanolamine, tris(hydroxymethyl)aminomethane or a polyamine, such as polyethyleneimine. If it is divalent, a countercation can salify two closed monovalent anionic groups.
- the counteranion of cationic groups is preferably selected from the group comprising a chloride, a sulfate, a phosphate or an acetate. If it is divalent, a counteranion can salify two closed monovalent cationic groups.
- pharmaceutically acceptable salts of the polymer encompasses all polymers with counterions associated with the ionized functions of the polymer. A total or partial neutralization of the charges can also be envisioned for certain structures where positive and negative charges coexist. A polymer having an equivalent number of positive charges and of negative charges (isoelectric point) can exist without the presence either of counteranion or countercation.
- the copolymers of the invention may be obtained, for example, using methods known to a person skilled in the art.
- N-carboxyamino acid anhydrides NCA
- the polymers are subsequently hydrolyzed under conditions appropriate for obtaining the polymer in its acid form.
- poly( ⁇ -L-glutamic), poly( ⁇ -D-glutamic), poly( ⁇ -D,L-glutamate) and poly( ⁇ -L-glutamic) with variable weights are available commercially.
- the copolymers of the invention may be synthesized according to two routes.
- the cationic group for example argininamide
- the B-GH group for example dodecylamine
- This reaction can take place in a solvent, such as DMF, DMSO or NMP, according to the following scheme.
- the precursor of the R 1 group such as ethanolamine linked via the nitrogen, is introduced during the synthesis at the same time as the cationic group.
- the cationic group comprises two amine functional groups that are not chemically differentiated (e.g. linear diamine), it can be introduced in a form in which one of the two functional groups is protected. A final stage of cleavage of the protective group is then added to the above scheme.
- the poly(L-glutamic acid) can be synthesized according to the route described in patent application FR-A-2 801 226. In cases where the HB-GH group is linked via an ester functional group, it is easier to first graft the B-GH group by a conventional coupling reaction using a carbodiimide, before grafting the cationic group.
- the precursor of the R 1 group such as ethanolamine linked via the nitrogen, is introduced during the synthesis at the same time as the cationic group.
- the cationic group comprises two amine functional groups which are not chemically differentiated (e.g. linear diamine), it can be introduced in a form in which one of the two functional groups is protected. A final stage of cleavage of the protective group is then added to the above scheme.
- the polymerization chemistry and the reactions for coupling the groups are conventional methods that are well known to a person skilled in the art (see, for example, the patents or patent applications of the Applicant mentioned above).
- the degree of polymerization is defined by the molar ratio of the initiator to that of the monomer.
- the coupling of a hydrophobic graft GH with an acid group of the polymer is easily carried out by reaction of the polyamino acid in the presence of a carbodiimide as coupling agent and, optionally, a catalyst, such as 4-dimethylaminopyridine, and in an appropriate solvent, such as dimethylformamide (DMF), N-methylpyrrolidone (NMP) or dimethyl sulfoxide (DMSO).
- a carbodiimide is, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide.
- Coupling reagents such as chloroformates
- Coupling reagents can also be used for the formation of amide bonds (see, for example, the work by Bodanszky, “Principles of Peptide Synthesis”, Springer Verlag, 1984, for examples of coupling agents).
- the degree of grafting is controlled chemically by the stoichiometry of the constituents and reactants or the reaction time.
- the hydrophobic grafts functionalized by an amino acid other than that of the polymer are obtained by conventional peptide coupling or by direct condensation by acid catalysis. These techniques are well known to a person skilled in the art.
- the invention is directed to a pharmaceutical, cosmetic, health food or plant-protection composition, which comprises at least one polyglutamate as defined above and optionally at least one active principle which can be a therapeutic, cosmetic, health food or plant-protection active principle.
- the active principle is associated with the polyamino acid(s) modified by a cationic group by one or more bonds other than (a) covalent chemical bond(s).
- the active principle is selected from the group consisting of: proteins, glycoproteins, proteins bonded to one or more polyalkylene glycol chains [preferably polyethylene glycol (PEG): “PEGylated proteins”], peptides, polysaccharides, liposaccharides, oligonucleotides, polynucleotides and mixtures thereof, and, more preferably still, from the subgroup of erytropoietins, such as epoetin alfa, epoetin beta, darbepoetin, hemoglobin raffiner, their analogs or their derivatives; oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), factors which stimulate hematopoiesis and mixtures thereof, blood factors, such as alteplase, tenecteplase, factor VII(a) or factor VII; hemoglobin, cytochromes, album
- Suitable active principles are polysaccharides (for example, heparin) and oligo- or polynucleotids, DNA, RNA, iRNA, antibiotics and living cells.
- Suitable active principles comprises pharmaceutical substances which act on the central nervous system, for example risperidone, zuclopenthixol, fluphenazine, perphenazine, flupentixol, haloperidol, fluspirilene, quetiapine, clozapine, amisulprid, sulpiride, ziprasidone, and the like.
- the active principle is a hydrophobic, hydrophilic or amphiphilic small organic molecule.
- a “small” molecule is in particular a small nonprotein molecule.
- APs that can associate with polyamino acids according to the invention, whether or not in the form of (nano- or micro)particles, include, but are not limited to:
- the active principle is selected from at least one of the following families of active substances: agents for the treatment of alcohol abuse, agents for the treatment of Alzheimer's disease, anesthetics, agents for the treatment of acromegaly, analgesics, antiasthlmatics, agents for the treatment of allergies, anticancer agents, antiinflammatories, anticoagulants and antithrombotics, anticonvulsants, antiepileptics, antidiabetics, antiemetics, antiglaucomas, antihistaminics, antiinfectives, antibiotics, antifungals, antivirals, antiparkinsonians, anticholinergics, antitussives, carbonic anhydrase inhibitors, cardiovascular agents, hypolipidemics, antiarythnmics, vasodilators, antianginals, antihypertensives, vasoprotectants, cholinesterase inhibitors, agents for the treatment of disorders of the central nervous system, stimulants of the central nervous system, contraceptives, fertility promoter
- a composition of the invention is in the form of a gel, solution, emulsion, micelles, nanoparticles, microparticles, implant, powder, suspension or film.
- a composition, loaded or not with active principle(s) is a stable colloidal suspension of polyamino acid nanoparticles and/or microparticles and/or micelles in an aqueous or oily phase.
- Microparticles can be obtained by various methods, such as coacervation in the presence of an aggregating agent (divalent or trivalent ions or polyelectrolytes), precipitation by change in pH or in the ionic strength, extraction/evaporation or atomization.
- an aggregating agent divalent or trivalent ions or polyelectrolytes
- precipitation by change in pH or in the ionic strength precipitation by change in pH or in the ionic strength
- extraction/evaporation or atomization extraction/evaporation or atomization.
- composition according to the invention can be a colloidal solution of nanoparticles in an aqueous phase at acidic pH which precipitates at physiological pH.
- a polyamino acid of the invention exhibiting an excess of cationic charges can condense an anionic active principle, such as DNA, a DNA fragment, an RNA or an oligo-RNA, in the form of nano- or microparticles and these particles can be internalized in a cell.
- an anionic active principle such as DNA, a DNA fragment, an RNA or an oligo-RNA
- the composition of the invention is in the form of a solution in a biocompatible solvent and can be injected subcutaneously or intramuscularly or into a tumor.
- composition according to the invention can be administered orally, parenterally, nasally, vaginally, ocularly, subcutaneously, intravenously, intramuscularly, intradermally, intraperitoneally, intracerebrally or buccally or by the pulmonary route.
- composition in the form of a solution in a biocompatible solvent or a mixture of biocompatible solvents capable of being injected subcutaneously or intramuscularly or into a tumor.
- the composition can optionally comprise an excipient for the adjustment of the pH and/or of the osmolarity and/or for improving the stability (antioxidants) and/or as antimicrobial agent.
- excipients are well known to a person skilled in the art (reference is made to the work: Injectable Drug Development , P. K. Gupta et al., Interpharm Press, Denver, Colo., 1999).
- the invention is also directed to a process for the preparation
- the invention also relates to a therapeutic method of treatment which consists essentially in administering the composition as described in the present account orally, parenterally, nasally, vaginally, ocularly, subcutaneously, intravenously, intramuscularly, intradermally, intraperitoneally, intracerebrally or buccally or by the pulmonary route.
- this therapeutic method of treatment consists essentially in employing the composition as described above in the form of a solution in a biocompatible solvent and then in injecting it subcutaneously or intramuscularly or into a tumor, preferably so that it forms a deposit on the injection site.
- the milky suspension of activated polymer is then added to this suspension and the reaction mixture is stirred at 0° C. for 2 h and then at 20° C. overnight.
- the reaction mixture is run dropwise into 1.6 l of water.
- the solution obtained is diafiltered against 8 volumes of aqueous saline solution (0.9%) and then 4 volumes of water, and concentrated to a volume of approximately 250 ml.
- the percentage of grafted argininamide, determined by proton NMR in D 2 O, is 90%.
- the solution obtained is diafiltered against 8 volumes of aqueous saline solution (0.9%) and then 4 volumes of water, and concentrated to a volume of approximately 50 ml.
- the percentage of grafted BOC-putrescine, determined by proton NMR in D 2 O, is 90%.
- Approximately 300 ml of a 48 mg/g concentrated solution are obtained, according to a procedure similar to that used for the synthesis of the polymer (1), starting from 10 g of a poly(glutamic acid) with a DP of 100 randomly grafted with 5% of racemic ⁇ -tocopherol, from 9.6 g of isobutyl chloroformate, from 7.7 ml of N-methylmorpholine, from 24.7 g of argininamide dihydrochloride and from 14.7 ml of triethylamine. The percentage of argininamide, determined by proton NMR in D 2 O, is 83%.
- Approximately 250 ml of a 43 mg/g concentrated solution are obtained, according to a procedure similar to that used for the synthesis of the polymer (1), starting from 10 g of a poly(glutamic acid) with a DP of 220 randomly grafted with 5% of racemic ⁇ -tocopherol, from 2.9 g of isobutyl chloroformate, from 2.2 ml of N-methylmorpholine, from 4.93 g of argininamide dihydrochloride and from 3.3 ml of triethylamine. The percentage of argininamide, determined by proton NMR in D 2 O, is 28%.
- Approximately 200 ml of a 41 mg/g concentrated solution are obtained, according to a procedure similar to that used for the synthesis of the polymer (3), starting from 10 g of a poly(glutamic acid) with a DP of 100 randomly grafted with 5% of racemic ⁇ -tocopherol, from 9.58 g of isobutyl chloroformate, from 7.7 ml of N-methylmorpholine, from 8.22 g of argininamide dihydrochloride, from 2.86 g of ethanolamine and from 5.1 ml of triethylamine.
- the percentages of argininamide and of ethanolamine, determined by proton NMR in D 2 O, are respectively 40 and 48%.
- Approximately 200 ml of a 51 mg/g concentrated solution are obtained, according to a procedure similar to that used for the synthesis of the polymer (1), starting from 10 g of a poly(glutamic acid) with a DP of 220 randomly grafted with 5% of racemic ⁇ -tocopherol, from 6.39 g of isobutyl chloroformate, from 5.1 ml of N-methylmorpholine, from 13.16 g of argininamide dihydrochloride and from 7.5 ml of triethylamine. The percentage of argininamide, determined by proton NMR in D 2 O, is 63%.
- the milky suspension of activated polymer is then added to this suspension and the reaction mixture is stirred at 0° C. for 2 h and then at 20° C. for 4 h.
- the solution obtained is diafiltered against 8 volumes of aqueous saline solution (0.9%) and then 4 volumes of water, and concentrated to a volume of approximately 250 ml.
- the percentage of grafted argininamide, determined by proton NMR in D 2 O, is 55%.
- the comparative compound C1 is the precursor (in its anionic form) of the polyglutamate modified by a cationic group, i.e. the polyglutamate with a DP of 220 randomly grafted with 5% of racemic ⁇ -tocopherol. This compound is obtained by the method described in application WO-A-03/104303.
- aqueous solution comprising 10 mg of polymer per milliliter at pH 7.4 and 200 IU of insulin (7.4 mg) is prepared.
- the solutions are left to incubate at room temperature for two hours and the free insulin is separated from the associated insulin by ultrafiltration (threshold at 100 kDa, 15 minutes under 10 000 G at 18° C.).
- the free insulin recovered in the filtrate is subsequently assayed by HPLC (High Performance Liquid Chromatography) and the amount of associated insulin is deduced.
- HPLC High Performance Liquid Chromatography
- RNA RNA-binding protein
- polymer (1) or (3) a quantity of polymer (1) or (3) is added to RNA, allowing complete association of the RNA (conditions in which RNA is not visible anymore at the gel expected size) and these mixtures are incubated for 2 hours at 37° C. After 2 hours at 37° C., increasing quantities of compound C1 are added to these mixtures and a new incubation of 16 hours at 37° C. is carried out.
- the mixtures obtained are analyzed by 1% agarose gel electrophoresis under denaturing conditions (revelations of RNA with ethidium bromide).
- results show, at the expected size, increasing quantities of RNA in correlation with the quantity of polymer C1 added to the mixture RNA/polymer (1) or (3).
- RNA oligonucleotide of 30 bases marked with Cy3 is mixed with a quantity of polymer (3) or (7) closed to the minimum quantity necessary to totally associate the oligonucleotide.
- This mixture is contacted on human hepatocarcinom cells Huh-7 grown on 24-well plates with 25 000 cell/well. After 4 hours of cell incubation at 37° C., 5% CO 2 , medium D-MEM at 20% of fetal calf serum (FCS) is added so as to the final concentration of FCS be 10%.
- FCS fetal calf serum
- DAPI nuclear DNA
- AlexaFluor®488 marked streptavidine which reveals the biotinyled concanavaline.
- Cells are analyzed by confocal microscopy.
- Cells are analyzed by confocal microscopy.
- Cy3 fluorescence excitation at 550 nm, emission at 570 nm.
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Abstract
Description
-
- to protect them from decomposition (hydrolysis, enzymatic digestion, and the like),
- and/or to control their rate of release, in order to maintain a therapeutic level over a defined period of time,
- and/or to convey them (while protecting them) to the site of action.
-
- ability:
- to easily and economically form stable aqueous colloidal suspensions,
- to easily associate with numerous active principles, and
- to release these active principles in vivo,
- biocompatibility,
- biodegradability,
- stability to hydrolysis.
- ability:
-
- at least 1% of cationic groups (molar %, with respect to glutamic acid residues) and up to 99%,
- on average, at least two pendant hydrophobic groups (GH) per molecule. It is possible, in accordance with the invention, for a polyglutamic acid to contain, in addition to pendant hydrophobic groups (GH), hydrophobic groups (GH) that are attached to at least one end of the copolymer chains.
in which —R10 is —H, —CO2H, alkyl ester (preferably —COOMe or —COOEt), —CH2OH, —C(═O)—NH2, —C(═O)—NH—CH3 or C(═O)—N(CH3)2.
-
- lowering the viscosity of the polymer for easier injection or easier use during the formulation stage,
- providing good association with neutral, anionic or cationic active principles.
-
- anionic, cationic or neutral and capable of associating with charged or uncharged active principles,
- cationic at moderately acidic pH (pH=4-5) and neutral or weakly charged at neutral pH. In this case, this dependence on the pH allows them, after association with the active principle in solution at pH=4-5, to form a deposit in a physiological medium.
-
- X═O, NH,
- Y=independently H or CH3,
- Z−=a chloride, a sulfate, a phosphate or an acetate,
- L=a linear (C2 to C6) alkylene optionally substituted by a functional carboxyl group or derivative thereof.
-
- wherein Ra is a hydroxy, alkoxy or alkylamino group, preferably —OMe, —OEt, —NH2, —NHCH3 or —N(CH3)2, and Z− is a chloride, a sulfate, a phosphate or an acetate, preferably a chloride,
or
—NH—(CH2)4—NH3 +,Z−,
—NH—(CH2)4—NH—C(═NH)—NH3 +,Z−,
—O—(CH2)2—N+(CH3)3,Z−,
—O—(CH2)2—NH3 +,Z−, - wherein Z− is a chloride, a sulfate, a phosphate or an acetate, preferably a chloride.
- wherein Ra is a hydroxy, alkoxy or alkylamino group, preferably —OMe, —OEt, —NH2, —NHCH3 or —N(CH3)2, and Z− is a chloride, a sulfate, a phosphate or an acetate, preferably a chloride,
in which Ra represents a hydroxy, alkoxy or alkylamino group, preferably an —OMe, —OEt, —NH2, —NHCH3 or —N(CH3)2 group.
-
- linear or branched C8 to C30 alkyls which can optionally comprise at least one unsaturation and/or at least one heteroatom,
- C8 to C30 alkylaryls or arylalkyls which can optionally comprise at least one unsaturation and/or at least one heteroatom,
- and C8 to C30 (poly)cyclic compounds which can optionally comprise at least one unsaturation and/or at least one heteroatom.
-
- in which:
- A independently represents:
- an RNH— group in which R is H, a linear C2 to C10 or branched C3 to C10 alkyl or a benzyl group,
- a terminal amino acid residue of formula:
- A independently represents:
- in which:
-
-
-
- in which
- —R7 is —OH, —OR9 or —NHR10, and
- R8, R9 and R10 independently are H, a linear C2 to C10 or branched C3 and
- C10 alkyl group or a benzyl group;
- B is a direct bond or a divalent, trivalent or tetravalent bonding group preferably chosen from the following groups:
- —O—, —NH—, —N(C1 to C5 alkyl)-, a residue of amino acid (preferably of a natural amino acid), of diol, of triol, of diamine, of triamine, of aminoalcohol or of hydroxy acid comprising from 1 to 6 carbon atoms;
- D is H, a linear C2 to C10 or branched C3 to C10 acyl group or a pyroglutamate;
- the hydrophobic groups (GH) each are, independently of one another, a group selected from:
- linear or branched C8 to C30 alkyls which can optionally comprise at least one unsaturation and/or at least one heteroatom (preferably O and/or N and/or S), or
- C8 to C30 alkylaryls or arylalkyls which can optionally comprise at least one unsaturation and/or at least one heteroatom (preferably O and/or N and/or S), or
- C8 to C30 (poly)cyclic compounds which can optionally comprise at least one unsaturation and/or at least one heteroatom (preferably O and/or N and/or S);
- preferably, this group is selected from the group consisting of: octanol, dodecanol, tetradecanol, hexadecanol, octadecanol, oleyl alcohol, tocopherol and cholesterol, B being a direct linked;
- R1 is a radical chosen from the following group of formulae:
—NH—(CH2)w—NH3 +,Z−,
in which w is between 2 and 6, preferably w is 4,
—NH—(CH2)4—NH—C(═NH)—NH3 +,Z−,
—O—(CH2)2—NH3 +,Z−,
—O—(CH2)2—N+(CH3)3,Z−,- an amino acid residue or an amino acid derivative of formula:
-
-
-
- in which:
- X is an oxygen atom or —NH—,
- R12 is H, linear C2 to C10 or branched C3 to C10 alkyl or benzyl,
- R13 is —(CH2)4—NH3 +, Z, —(CH3)3—NH—C(═NH)—NH3 +, Z−, —(CH2)3—NH3 +, Z−;
- in which the counteranion Z− is a chloride, a sulphate, a phosphate or an acetate, preferably a chloride;
- R3 is hydroxyethylamino-, alkylene glycol, polyalkylene glycol or a group of formula:
in which —R10 is —H, —CO2H, an alkyl ester (preferably —COOMe or —COOEt), —CH2OH, —C(═O)—NH2, —C(═O)—NH—CH3 or —C(═O)—N(CH3)2;
-
- p, q, r and s are positive integers;
- (p)/(p+q+r+s) is defined as the molar degree of grafting of the hydrophobic groups GH and varies from 2 to 99 molar % and preferably between 5 and 50 molar %, provided that each copolymer chain has, on average, at least 3 hydrophobic grafts;
- (q)/(p+q+r+s) is defined as the molar degree of grafting of the cationic groups and varies from 1 to 99 molar %;
- (p+q+r+s) varies from 10 to 1000, preferably between 30 and 500;
- (r)/(p+q+r+s) varies from 0 to 98 molar %;
- (s)/(p+q+r+s) varies from 0 to 98 molar %
and pharmaceutically acceptable salts thereof.
- “Microspheres, Microcapsules and Liposomes; Vol. 1. Preparation and Chemical Applications”, edited by R. Arshady, Citus Books, 1999. ISBN: 0-9532187-1-6.
- “Sustained-Release Injectable Products”, edited by J. Senior and M. Radomsky, Interpharm Press, 2000. ISBN: 1-57491-101-5.
- “Colloidal Drug Delivery Systems” edited by J. Kreuter, Marcel Dekker, Inc., 1994. ISBN: 0-8247-9214-9.
- “Handbook of Pharmaceutical Controlled Release Technology”, edited by D. L. Wise, Marcel Dekker, Inc., 2000. ISBN: 0-8247-0369-3.
-
- aqueous dissolution of AP and then addition of the VPs, either in the form of a colloidal suspension or in the form of isolated VPs (lyophilizate or precipitate);
- or addition of AP, either in solution or in the pure or preformulated state, to a colloidal suspension of VP particles optionally prepared at the time of use by the dispersion of dry VPs in an appropriate solvent, such as water.
-
- proteins, such as insulin, interferons, growth hormones, interleukins, erythropoietin or cytokines;
- peptides, such as leuprolide or cyclosporin;
- small molecules, such as those belonging to the family of the anthracyclines, taxoids or camptothecins;
- and mixtures thereof.
-
- of medicaments, in particular for oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal or intracerebral administration, wherein the active principles of these medicaments can be in particular proteins, glycoproteins, proteins linked to one or more polyalkylene glycol chains {for example, PolyEthylene Glycol (PEG); the term then used is “PEGylated” proteins}, peptides, polysaccharides, liposaccharides, oligonucleotides, polynucleotides and hydrophobic, hydrophilic or amphiphilic small organic molecules;
- and/or nutriments;
- and/or cosmetic or plant-protection products;
wherein the process consists essentially in employing at least one of the polyamino acids as defined above and/or the composition described above.
TABLE 1 | |||
Polymer | % association | ||
3 | 100% | ||
6 | 96% | ||
8 | 100% | ||
C1 | 99% | ||
Example |
C1 | 3 | 6 | 8 | 10 | ||
Viscosity | 4720 | 6.6 | 4.5 | 5.8 | 4.7 | ||
Polymer | pH = 4 | Physiological pH |
1 | soluble | soluble |
2 | soluble | soluble |
3 | soluble | soluble |
4 | soluble | soluble |
5 | soluble | soluble |
6 | insoluble | soluble |
7 | soluble | soluble |
8 | soluble | soluble |
9 | soluble | insoluble |
10 | soluble | insoluble |
C1 | insoluble | soluble |
Claims (18)
—NH—(CH2)4—NH3 +,Z−,
—O—(CH2)2—N+(CH3)3,Z−,
—O—(CH2)2—NH3 +,Z−,
—NH—(CH2)w—NH3 +,Z−,
—NH—(CH2)4—NH—C(═NH)—NH3 +,Z−,
—O—(CH2)2—NH3 +,Z−,
—O—(CH2)2—N+(CH3)3,Z−,
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NZ580906A (en) | 2011-07-29 |
AU2008248604B2 (en) | 2012-11-08 |
FR2915748A1 (en) | 2008-11-07 |
BRPI0809208A2 (en) | 2016-11-16 |
WO2008135563A1 (en) | 2008-11-13 |
FR2915748B1 (en) | 2012-10-19 |
EP2152782A1 (en) | 2010-02-17 |
IL201017A0 (en) | 2010-05-17 |
IL201017A (en) | 2013-03-24 |
AU2008248604A1 (en) | 2008-11-13 |
ZA200906941B (en) | 2010-12-29 |
US20090012028A1 (en) | 2009-01-08 |
KR20100016280A (en) | 2010-02-12 |
CA2683741A1 (en) | 2008-11-13 |
CN101663346A (en) | 2010-03-03 |
JP2010529214A (en) | 2010-08-26 |
EA016911B1 (en) | 2012-08-30 |
CN101663346B (en) | 2012-03-21 |
EA200901481A1 (en) | 2010-04-30 |
MX2009011813A (en) | 2009-11-13 |
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